The Effects of Prenatal Exposure of Valproic Acid on Cranial Nerve Nuclei: A Rat Model for an Autistic Phenotype

Autistic spectrum disorder is a term referring to five pervasive developmental disorders characterized by impairment in social interaction, deficits in verbal and non-verbal communication and stereotyped repetitive behaviors and interests. The underlying brain injury that leads to autism is also unknown. The cause is also unknown but appears to be a combination of genetic and environmental factors. A study on prenatal thalidomide exposure found patients exposure on days 20-24 of gestation lead to a 1/3 rate of autism, a huge increase from the 1/150 rate of the general population. The thalidomide data suggests the initial injury leading to autism occurs during this window of gestation, a time correlating with the period of neural tube closure and development of the neurons of the cranial nerve nuclei. Thalidomide is non-teratogenic in rats so to reproduce similar brain injury in animals we exposed rats to valproic acid. Dams were given a single large dose of valproic acid on a single day of gestation from G9-G13 inclusive. These gestational days correlating with the time just before neural tube closure through the development of the first neurons of the cranial nerve motor nuclei to check for time dependent effects. We analyzed two motor nuclei: the facial (VII) and the trigeminal (V) nuclei; and three sensory nuclei: the principal sensory nuclei of the spinal trigeminal, and the oral and interpolar subnuclei of the spinal trigeminal complex. Treatment revealed a decrease in neuronal cell number in the oral and interpolar subnuclei of the trigeminal on G13. No differences were found in the motor nuclei or the PSN. This suggests multiple rhombomere selection and alar plate susceptibility